Multiple sclerosis (MS) is a disease characterized by inflammation and demyelination in central nervous system white matter. Indirect evidence suggests that the immune system plays a role in the pathogenesis of MS, and data from family all twin studies indicate that genetic factors are important determinants of MS susceptibility This study will attempt to establish the chromosomal location of the MS susceptibility gene or genes by linkage analysis using the affected sib pair method. Forty families, each with two siblings affected with typical MS, will be studied initially, and it is anticipated that accrual of an additional 20 families per year will be possible. Limphoblastoid lines will be established from all individuals. Using DNA polymorphisms, affected siblings will be studied for co-inheritance of candidate susceptibility genes including the alpha, beta and gamma chain genes of the T-cell receptor, and traditional typing methods will bemused to assess inheritance of HLA and immunoglobulin genes. Restriction fragment length polymorphisms will bemused to study other genes encoding proteins important for T-cell function, oncogenies, and myelin- related genes. Should no candidate genomic region: be identified the entire genes will be searched for markers linked to MS susceptibility, with emphasis placed on the use of highly polymorphic, appropriately spaced probes. These probes will include those detecting variable number tandem repeat" sequences. Identification of a genetic marker linked to MS susceptibility should provide a direct approach to the characterization of the susceptibility gene and to an understanding of its role in the pathogenesis of MS.